IE960540A1 - A formulation - Google Patents

Abstract

A transdermal patch contains aspirin as a pharmaceutically active product having platelet washing properties. The patch comprises a backing, an adhesive for applying the patch and a liner which is released to apply the patch. The aspirin is incorporated into the adhesive.<Fig.1>

Description

Aspirin, which has been available for about 100 years, possesses analgesic, anti-inflammatory and antipyretic properties. This compound has also been shown to be effective in cardiovascular disease and this action is dependent upon its effects on platelet function. Aspirin can improve the mortality figures associated with acute myocardial infarction and reduces the risk of this in patients with unstable angina by between 30 and 50%. It is used to prevent re-occurrence in those patients after recovery from myocardial infarction. It is also likely to be of benefit to individuals suffering from stable angina since it reduces the risk of myocardial infarction in apparently healthy, middle-aged men. Aspirin is used to reduce the likelihood of stroke in patients with transient cerebral ischaemic attacks. It also lowers the risk of thromboembolism in patients with atrial fibrillation and following valve replacement.

Aspirin reduces platelet aggregation by irreversibly inhibiting fatty acid cyclo-oxygenase, a precursor in the biosynthesis of prostaglandins and thromboxanes. This occurs by acetylation of a serine residue and thus prevents access of arachidonic acid to the active site by steric hindrance. Thromboxane A2 is the main cyclo25 oxygenase produce of activated platelets and is proaggregatory and a vasoconstrictor. Therefore, aspirin exerts its antithrombotic action by preventing thromboxane A2 biosynthesis. Although other non-steroidal antiinflammatory drugs also possess this effect they are much less effective because, unlike aspirin, they reversibly inhibit the enzyme.

T J «<ΙΙΙ·1Ι.«~·||Ι - 2 Although the use of oral aspirin has been used for these conditions, there are a number of disadvantages associated with this treatment. The compound has been associated with various gastrointestinal side effects the most severe of which can be gastric bleeding occurring in about 70% of patients taking oral aspirin. Furthermore, the drug is extensively hydrolysed by first-pass metabolism and possesses a half life of about 15 minutes. Salicylic acid, a metabolite of aspirin, has no anti-platelet activity.

Therefore, the development of a suitable transdermal delivery system for aspirin would avoid the side-effects detailed above and would also prevent first-pass metabolism.

According to the invention, there is provided a transdermal patch containing aspirin as a pharmaceutically active product having platelet washing properties, the patch comprising a backing, an adhesive for applying the patch and a liner which is released to apply the patch, wherein the aspirin is incorporated into the adhesive.

The invention also provides a transdermal patch for sustained transdermal administration of aspirin to a patient in need of platelet washing effect comprising a backing, an adhesive for applying the patch, and a liner which is released to apply the patch, in which aspirin is incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels .

The invention further provides use of aspirin for preparing a transdermal patch comprising a backing, an adhesive for applying the patch, and a liner which is released to apply the patch, in which aspirin is - 3 incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

In another aspect, the invention provides a method for achieving a platelet washing effect in a patient comprising the step of applying a transdermal patch comprising a backing, an adhesive for applying the patch and a liner which is released to apply the patch to the patient's skin, aspirin being incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

Preferably the adhesive is a pressure sensitive adhesive, based, for example, on acrylic acid copolymers.

In one embodiment of the invention, the adhesive is applied to the release liner. Typically, the release liner is a fluoro-polymeric-coated polyester.

Preferably, the backing comprises a backing layer attached to the adhesive. Typically the backing layer comprises aluminised polyester. In one case the aluminised polyester is sputter coated onto the adhesive.

In another embodiment of the invention the patch includes a penetration enhancer to promote the diffusion of the pharmaceutically active product.

The invention also provides a method for producing a transdermal patch comprising the steps of incorporating a pharmaceutically active product having platelet washing properties into an adhesive.

The invention further provides a transdermal patch whenever produced by the method of the invention. - 4 In another aspect, the invention provides a method for reducing platelet aggregation in a patient comprising the step of applying to a patient a transdermal patch of the invention.

The purpose of the present invention is to develop a stable transdermal patch system which will deliver sufficient aspirin to the systemic circulation to reduce platelet aggregation. It is a further purpose of this invention to deliver sufficient aspirin to inhibit thromboxane A2 production associated with the platelets but not prostacyline production occurring within the venous endothelium.

The invention will be more clearly understood from the following description thereof given by way of example only with reference to Fig. 1 which is a diagrammatic cross sectional view of a transdermal patch according to the invention.

Referring to Fig. 1, there is illustrated a transdermal patch according to the invention comprising a pressure sensitive adhesive layer (b) into which the aspirin is incorporated, a release liner (c) and a backing (a).

Aspirin has been incorporated directly into a pressure sensitive adhesive such as, but not limited to, acrylic acid copolymers (b) . This mixture can then be cast, rolled or knife-coated onto a suitable release-liner such as, but not limited to, a siliconised polyester (c). A backing-layer such as, but not limited to, a sputtercoated aluminised polyester (to prevent drug strike through) can then be attached (a). The release-liner (c) is removed before the drug containing adhesive is presented to the skin. - 5 Unusually, this patch has been designed so that skin acts as the rate-determining membrane to drug diffusion. The advantage of this type of system is that it provides the most efficient delivery of drug through the skin. This, in turn, will provide the smallest unit area of skin for drug delivery and hence the smallest patch size. This is an important consideration given the possible daily amounts of drug required by the transdermal route. A further advantage of this invention is that aspirin can be delivered systemically avoiding first-pass metabolism. Furthermore, delivering aspirin transdermally will also prevent adverse side-effects on the gastrointestinal tract.

A further aspect to this invention is the use of various penetration enhancers to promote the diffusion of aspirin through the skin to the systemic circulation. This would also reduce the size (area) of patch required to deliver a given amount of aspirin to the systemic circulation. Examples of such penetration enhancers include, but is not limited to, propylene glycol, oleic acid, isopropyl myristate, dimethylsulphoxide, ethanol, and/or limonene.

A variety of suitable matrices may be used as a drug reservoir. These include the above mentioned acrylate copolymers, polyisobutylenes and silicone-based adhesives. Other excipients present in the formulation may include plasticisers such as diethylphthalate, dibutylphthalate, glycerol.

Example 1 A transdermal delivery system for aspirin was prepared in the following way. A pressure sensitive adhesive solution (PSA) was prepared using Duro-Tak 387-2054 dissolved in ethyl acetate. Aspirin (200 mg) was dissolved in 20 g of - 6 PSA and cast onto a siliconised release liner using a 10 x 10 cm template. The film was oven dried after which an aluminium sputter-coated polyester backing layer was attached to the exposed, drug-containing, adhesive film (dry weight 5 g) . Thereafter, 1 cm2 sections were cut from the laminate and examined for drug release using siliconebased (Silescol) sheeting in a modified Franz cell (Fig. 2).

Patches (5x5 cm2) were also applied to 5 human volunteers 10 for a 24 hour period. Thereafter, the patches were removed and extracted for remaining aspirin. It can be seen from Fig. 3 that, typically 30 - 40% of the drug had been absorbed from the patches within a 24 hour period.

DURO-TAK are a range of adhesives available from National 15 Starch.

Silescol is manufactured by Esco Rubber and is available from Bibby Sterilin.

The invention is not limited to the embodiments hereinbefore described which may be varied in detail.

Claims (20)

1. A transdermal patch containing aspirin as a pharmaceutically active product having platelet washing properties, the patch comprising a backing, an adhesive for applying the patch and a liner which is released to apply the patch, wherein the aspirin is incorporated into the adhesive.

2. A transdermal patch as claimed claim 1 wherein the adhesive is a pressure sensitive adhesive.

3. A transdermal patch as claimed in claim 2 wherein the adhesive is based on acrylic acid copolymers.

4. A transdermal patch as claimed in any preceding claim wherein the adhesive is applied to the release liner.

5. A transdermal patch as claimed in any preceding claim wherein the release liner is a fluoropolymeric-coated polyester.

6. A transdermal patch as claimed in claim 5 wherein the liner is a siliconised release liner.

7. A transdermal patch as claimed in any preceding claim wherein the backing comprises a backing layer attached to the adhesive.

8. A transdermal patch as claimed in any preceding claim wherein the backing layer comprises aluminised polyester.

9. A transdermal patch as claimed in claim 8 wherein the aluminised polyester is sputter coated onto the adhesive.

10. A transdermal patch as claimed in any preceding claim including a penetration enhancer to promote the diffusion of the pharmaceutically active product.

11. A transdermal patch as claimed in claim 10 wherein the penetration enhancer is selected from one or more of propylene glycol, oleic acid, isopropyl myristate, dimethylsulphoxide, ethanol and/or limonene.

12. A transdermal patch substantially as hereinbefore described with reference to the example and drawings .

13. A method for producing a transdermal patch comprising the steps of incorporating a pharmaceutically active product having platelet washing properties into an adhesive, coating the adhesive onto a release liner, and applying a backing layer.

14. A method for producing a transdermal patch substantially as hereinbefore described with reference to the examples and drawings.

15. A transdermal patch whenever produced by a method as claimed in claim 13 or 14.

16. A method for reducing platelet aggregation in a patient comprising the step of applying to a patient a transdermal patch as claimed in any of claims 1 to 12 or 15.

17. A method for reducing platelet aggregation in a patient substantially as hereinbefore described with - 9 reference to the examples and drawings.

18. A transdermal patch for sustained transdermal administration of aspirin to a patient in need of platelet washing effect comprising a backing, an 5 adhesive for applying the patch, and a liner which is released to apply the patch, in which aspirin is incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

19. Use of aspirin for preparing a transdermal patch comprising a backing, an adhesive for applying the patch, and a liner which is released to apply the patch, in which aspirin is incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.

20. A method for achieving a platelet washing effect in a patient comprising the step of applying a transdermal patch comprising a backing, an adhesive for applying the patch and a liner which is released 20 to apply the patch to the patient's skin, aspirin being incorporated in the adhesive in an amount sufficient to transdermally permeate the skin and achieve desired plasma levels.